The present application relates to a shortened process for producing prostacyclin derivatives and novel intermediate compounds useful in the process. The present application also relates to stereoselectively produced compounds prepared by the inventive process. Furthermore, the prostacyclins produced in this process are pure diastereomers, i.e.,  greater than 99%.
Prostacyclin derivatives are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, vasodilation and bronchodilation.
For convenience, the novel prostacyclin derivatives will be referred to by the trivial, art-recognized system of nomenclature described by N. A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF1-type compounds.
U.S. Pat. No. 4,306,075 discloses methods for making prostacyclin derivatives. However, these and other known processes involve a large number of steps. It is an object of the present invention to provide an improved method of preparing prostacyclin derivatives involving fewer steps.
The present invention relates to a process for preparing 9-deoxy-PGF1-type compounds by a process that is stereoselective and requires fewer steps than the prior art. The invention also relates to novel intermediates prepared during the synthesis of the 9-deoxy-PGF1-type compounds. Furthermore, the invention relates to 9-deoxy-PGF1-type compounds prepared by the inventive process.
In one embodiment, the present invention relates to an improved stereoselective method for making 9-deoxy-PGF1-type compounds comprising converting a compound of the formula: 
into a compound of the following formula: 
wherein Y1 is trans-CHxe2x95x90CHxe2x80x94, cis-CHxe2x95x90CHxe2x80x94, xe2x80x94CH2(CH2)mxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94; m is 1,2, or 3;
wherein R1 is H or an alcohol protecting group;
wherein R7 is
(1) xe2x80x94CpH2pxe2x80x94CH3, wherein p is an integer from 1 to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different,
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis-CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH3,
(5) xe2x80x94(CH)2xe2x80x94CH(OH)xe2x80x94CH3, or
(6) xe2x80x94(CH)3xe2x80x94CHxe2x95x90C(CH3)2;
wherein xe2x80x94C(L1)xe2x80x94R7 taken together is
(1) (C4-C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
wherein M1 is xcex1-OH:xcex2-R5 or xcex1-R:xcex2-OH or xcex1-OR1:xcex2-R5 or xcex1-R5:xcex2-OR1, wherein R5 is hydrogen or methyl and R1 is an alcohol protecting group; and
wherein L1 is xcex1-R3:xcex2-R4, xcex1-R4:xcex2-R3, or a mixture of xcex1-R3:xcex2-R4 and xcex1-R4:xcex2-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro.
Preferably, the above conversion is carried out through cobalt-mediated cyclization, in which the enyne undergoes intramolecular cyclization accompanied by a carbon monoxide insertion to form the tricyclic structure shown below. 
More preferably, this cyclization is carried out by reacting Co2(CO)8 with a compound of the formula: 
using a suitable non-reactive solvent. Preferably, the non-reactive solvent is a chlorinated solvent, a hydrocarbon solvent, or an aromatic solvent. More preferably, the non-reactive solvent is selected from the group consisting of 1,2-DME (1,2-dimethoxyethane), CH2Cl2, toluene, isooctane, and heptane.
In the case of carrying out the cobalt-mediated cyclization with 1,2-DME after reacting Co2(CO)8 with the compound of the formula: 
to form a complex with the alkynyl group, preferably the solvent is removed in a subsequent step after intramolecular cyclization occurs to form the tricyclic compound.
Although Co2(CO)8 contributes a carbonyl during the reaction, it is not necessary to react equal amounts of the starting compound of the above formula and Co2(CO)8. It is also possible to use the Co2(CO)8 in a catalytic way, by introducing a relatively small amount of Co2(CO)8 and also introducing CO into the reaction mixture (e.g., by bubbling CO into the reaction mixture) in the presence of light or heat which causes the transfer of CO through a Co-mediated complex formed with the compound of the formula: 
In another preferred embodiment, the present invention relates to an improved stereoselective method for making 9-deoxy-PGF1-type compounds comprising the following reaction with heat or light: 
wherein Y1 is trans-CHxe2x95x90CHxe2x80x94, cis-CHxe2x95x90CHxe2x80x94, xe2x80x94CH2(CH)mxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94; m is 1,2, or 3;
wherein R1 is an alcohol protecting group;
wherein R7 is
(1) xe2x80x94CpH2pxe2x80x94CH3, wherein p is an integer from 1 to 5, inclusive,
(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same or different,
(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
(4) cis-CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH3,
(5) xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94CH3, or
(6) xe2x80x94(CH2)3xe2x80x94CHxe2x95x90C(CH3)2;
wherein xe2x80x94C(L1)xe2x80x94R7 taken together is
(1) (C4-C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)alkyl;
(2) 2-(2-furyl)ethyl,
(3) 2-(3-thienyl)ethoxy, or
(4) 3-thienyloxymethyl;
M1 is xcex1-OH:xcex2-R5 or xcex1-R5:xcex2-OH or xcex1-OR1:xcex2-R5 or xcex1-R5:xcex2-OR1, wherein R5 is hydrogen or methyl and R1 is an alcohol protecting group;
wherein L1 is xcex1-R3:xcex2-R4, xcex1-R4:xcex2-R3, or a mixture of xcex1-R3:xcex2-R4 and xcex1-R4:xcex2-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro.
The present invention also relates to a method of making the following compounds utilizing the following reaction scheme: 
wherein R1 is in each case an independently selected alcohol protecting group. Preferred alcohol protecting groups are tertiary butyl dimethyl silyl (TBDMS) and tetra hydro pyranyl (THP), trimethylsilyl (TMS), TES or any bulky groups.
The present invention also relates to the following novel intermediate compounds: 
wherein Y1, M1, L1, R1 and R7 are as defined above.
The present invention also relates to a stereoselectively produced compound according to the following formula: 
wherein Z is O, S, CH2, or NR8 in which R8 is H, alkyl or aryl;
X is H, CN, OR9, or COOR9 in which R9 is alkyl, THP or TBDMS;
n is 0, 1, 2, or 3;
Y1, M1, L1, and R7 are as defined above and the compound is produced according to the inventive stereoselective synthesis. The produced compounds are diastereomerically pure.
In a preferred embodiment of the stereoselectively produced isomeric compound, Z is O, n is 1, X is COOH, Y1 is xe2x80x94CH2CH2xe2x80x94M1 is xcex1-OH:xcex2-R5, wherein R3 is hydrogen, L1 is xcex1-R3:xcex2-R4, wherein R3 and R4 are hydrogen and R7 is propyl. The stereoselectively produced isomeric compound is diastereomerically pure.
xe2x80x9cDiastereomerically pure, i.e.,  greater than 99%xe2x80x9d means that the present diastereoselective synthesis produces diastereomers as represented by the above formula having  greater than 99% purity. The purity level is determined by running the product through a chiral HPLC column where  greater than 99% of the above diastereomer exits the column as a single peak. A diastereoselective or stereoselevtive synthesis involves one or more reactions that yield predominantly one diastereomer or stereoisomer of several possible disatereomers or stereoisomers.